This proposal focuses on the NMDA subtype of neurotransmitter receptor, which is the key trigger for a number of synaptic plasticity events in mammalian brain, and in wiring up the normal brain neuronal circuitry during development. Synaptic modulation can occur by changes to the presynaptic neurotransmitter-releasing element or to the postsynaptic receptive element, or to both. Such synaptic modulation provides a strengthening of the lines of communication from one nerve cell to another. Examination of a process that is likely to strengthen neuronal communication by increasing the responsiveness of the neurotransmitter receptors on the postsynaptic receptive cell continues to be a key topic of interest in our laboratory. Protein kinases often regulate enzymes and also ion channels by placing a negatively charged phosphate group at key positions in the protein target. Our main focus is on modulation of the NMDA subtype of glutamate receptor by protein kinases of the "C type". Because repeated efforts by a number of laboratories have previously failed to find phosphorylation sites that mediate modulation of NMDA currents, some scientists hold the view that the often-demonstrated enhancement by kinases must be an indirect effect via associated proteins. However, my laboratory has now demonstrated that phosphorylation of specific serine residues by protein kinase C will allow current amplification in both NR2B- and NR2A-containing receptors. This potentiation of current occurs to differing degrees and under different regulatory control by kinases for NR2B vs. NR2A. This result 1) challenges the view that kinase modulation must be entirely indirect, 2) provides a starting point for elucidating a mechanism of direct kinase action, and 3) provides specific targets for development of pharmacological intervention that may hold more immediate promise than genetic intervention for memory enhancement, in the treatment of, for example, Alzheimer's disease. The development of a mouse model of PKC-resistant NMDA receptors to study the role of PKC regulation of NMDA receptors will be useful for a variety of studies from synaptic electrophysiology to animal behavior and from neural development, and cell death to learning and memory. These mice will be made available as a research tool for neuroscientists worldwide.